ProjectAbstract Oldageisthesinglegreatestriskfactorformanydiseasesincludingperiodontaldisease,dementia, diabetes,andheartdisease.Agingisassociatedwithfailuretomaintainhomeostasis,andoneresultisthe senescenceoftheimmunesystem,whichresultsin?inflammaging.?Bydelayingorreversingthebiological agingprocesses,suchasinflammaging,itmaybepossibletoreducetheimpactofage-relateddiseases, whichcouldhaveprofoundbenefitsforqualityoflife. ThemechanisticTargetofRapamycin(mTOR)hasbeenestablishedasanevolutionarilyconserved regulatoroflongevitythroughstudiesshowingthatreducingmTORactivityextendlifespanandimprove healthspanininvertebratesandmice.Rapamycin,aspecificinhibitorofmTOR,isapromisingcandidatefor delayingage-relateddiseasesandmayact,atleastinpart,byreducinginflammaging.Anage-associated inflammatorydiseaseintheoralcavityisperiodontaldisease.RecentepidemiologicdataintheU.S.revealed 64%ofadultsaged65yearsandolderhadperiodontitis.Hereweproposetotestthehypothesisthat mTORhyperactivationduringagingleadstoimmunecellsenescence,inflammation,andultimately leadstodetrimentalchangestotheoralmicrobiomethatunderliesoralpathologyduringaging. ThiswillbeaccomplishedfirstbyassessingmTORsignalingintheperiodontiumduringagingthrough quantificationofphosphorylationofmTORpathwaycomponentsandinflammatorymarkers.Todetermineif theperiodontiumofnormallyagedmiceiscomparabletoaninducedinflammatorystate,comparisonofaged rodentstoaligature-inducedperiodontitismodelwillbecompleted.Inpreliminarystudies,wehaveshownthat age-associatedperiodontalbonelossinmicewasimprovedafterrapamycintreatment.Thus,theabilityof rapamycintoattenuateage-associatedoralpathologyandeffectsoninnateimmuneresponseinligature- inducedperiodontitiswillbeexplored.Furthermore,theconsequenceofagingandmTORinhibitionontheoral microbiomewillbeinvestigated. TheproposedF30projectwasdevelopedtohelpprovideafoundationforanaspiringdentist-scientist andcontributetounderstandingthemechanisticandmolecularbasisforage-associatedchangesinthe periodontium.InvestigatingmTORsignalingintheperiodontium,andunderstandingtheroleofrapamycinin delayinginflammagingintheoralcavitywillhaveasignificantimpactonthefieldsofgeroscienceanddentistry, andcouldpotentiallyyieldmajorimprovementsinpublichealth.Withstronginstitutionalsupportfromthe UniversityofWashingtonandexcellentmentorship,weareconfidentthatthisF30awardwillaidinthebasic sciencesandclinicaltrainingrequiredtobeasuccessfuldentist-scientist.